Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC([NH:37][C:38]1([C:41]([OH:43])=O)[CH2:40][CH2:39]1)=O)(C)(C)C.[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:64])([F:63])[F:62])[CH:47]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH:56][C:41]([C:38]3([NH2:37])[CH2:39][CH2:40]3)=[O:43])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:62])([F:63])[F:64])[CH:47]=1
Reactant: COc1ccc(Oc2ccc(CN)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
540 μL (3.85 mmol) of triethylamine and 864 mg (2.69 mmol) of TBTU were added to a solution of 541.5 mg (2.69 mmol) of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid in 45 mL DMF and the mixture was stirred for 5 min at RT. Then 800 mg (2.69 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamine (from 84a) was added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down. 20 ml dichloromethane/trifluoroacetic acid/water=50/45/5 were added to the residue and the mixture was stirred for 1 h at RT. The reaction mixture was evaporated down, the residue was dissolved in dichloromethane and extracted with 10 mL of 1 M sodium hydroxide solution. The dichloromethane phase was separated off and evaporated down.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(=O)(=O)(O)O>O.C(O)(C)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 12.5 °C
Yield: 89.9 %

Procedure:
L-Arginine (50 g) was added with t-butyl alcohol (315 g) and water (125 g). The reaction mixture was added dropwise with lauroyl chloride (69 g) and 27 wt % aqueous sodium hydroxide (50 g) over 1 hour and 20 minutes, while the system was maintained at 10 to 15° C. and pH 10 to 11. After the addition, the reaction mixture was warmed to 45° C., added with sulfuric acid (17 g) and uniformly dissolved. Then, the system was adjusted to pH 4.9 with further addition of 27 wt % aqueous sodium hydroxide. The deposited crystals were collected by filtration and washed with water to obtain white crystals (92 g, yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>O1CCCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred solution of 2-amino-5-nitrobenzenethiol (1.72 g, 10.11 mmol) in tetrahydrofuran (10 mL) was added sodium bicarbonate (2.80 g, 33.4 mmol) as a solution in water (40.0 mL). To this dark red solution was added 2-chloroacetyl chloride (0.885 mL, 11.12 mmol). The resulting mixture, which turned faint red, was then stirred at room temperature overnight. The mixture was then diluted with water and extracted three time with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 10% ethyl acetate in dichloromethane, giving the desired product (1.02 g, 48.0%). 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.07 (dd, J=9.0, 2.7 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 3.60 (s, 2H); MS-EI: (m/z, %) 210 (M+, 100), 181 (40), 131 (46).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:28])[N:9]=1.C1COCC1.O[Li].O.Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:28])[N:9]=1
Reactant: CCOC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3F)nn(C)c2n1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of ethyl 2-(3-(2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetate (180 mg, 0.45 mmol) in a mixture of EtOH, THF and water (2 ml/1 ml/0.5 ml) was added LiOH.H2O (76.1 mg, 1.81 mmol). The reaction mixture was stirred for 1 h at rt. Aqueous HCl was then added to adjust the reaction mixture to pH ˜2. The resulting precipitate was filtered off and washed twice with pentane (2×10 mL). The obtained solid was dried under vacuum to furnish 130 mg (78%) of the title compound. [1H-NMR (CDCl3, 300 MHz) δ 7.58-6.95 (m, 5H), 5.25 (s, 2H), 4.15 (s, 3H); LCMS RtA=1.681 min; [M+H]+=370.1]
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][C:5]([Br:9])=[C:6]([Br:8])[CH:7]=1.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:9][C:5]1[C:6]([Br:8])=[CH:7][C:2]([Br:1])=[C:3]([F:21])[N:4]=1
Reactant: Nc1nc(Br)c(Br)cc1Br
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1nc(Br)c(Br)cc1Br
Yield: 84 %

Procedure:
The reaction and post-treatment were carried out according to Example (8a) using 3,5,6-tribromopyridin-2-amine produced in Example (15a) (2.34 g, 7.07 mmol), sodium nitrite (0.73 g, 10.6 mmol) and hydrogen fluoride-pyridine (5 mL) to obtain the title compound (1.98 g, 84%) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:17][CH2:18][C@@H:19]([OH:36])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCCC1=O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][C@H:19]([OH:36])[CH2:18][NH:17][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([C:14]([OH:16])=[O:15])=[CH:2][CH:3]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c2ccccc12
Reaction time: 16 h
Yield: 21 %

Procedure:
To a solution of naphthalene-1,4-dicarboxylic acid (0.100 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.147 g) and triethylamine (0.193 mL) in N-methyl-2-pyrolidinone (20 mL) was added PyBrOP (0.258 g). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to afford the title compound as a colourless solid (0.050 g, 20%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.414 ml, 4.24 mmol) is added to (R)-{3-[7-fluoro-1-(2-fluoro-ethyl)-2-oxo-2,3-dihydro-1H-indol-5-ylamino]-2-hydroxy-propyl}-carbamic acid tert-butyl ester (0.150 g, 0.424 mmol) and triethylamine (0.295 ml, 2.12 mmol) in dichloromethane (3 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.70 min; MS for C19H23F2N3O5 m/z 380.3 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[CH3:22])[C:3]([O:5][CH3:6])=[O:4].[N:23]([O-:25])=[O:24].[Na+].C1(C=C(O)C=C(O)C=1)O.O>CN(C)C=O>[CH3:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[O:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:2]([N+:23]([O-:25])=[O:24])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)c1ccccc1COc1cc(C)ccc1C
Reactant: O=N[O-]
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1COc1cc(C)ccc1C)[N+](=O)[O-]
Yield: 22.1 %

Procedure:
A solution of methyl 2-chloro-2-[2-(2,5-dimethylphenoxymethyl)phenyl]acetate (0.35 g, 1.1 mmol), sodium nitrite (0.13 g, 1.9 mmol) and phloroglucinol (0.145 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 hours. Water was added to the mixture. The resulting mixture was extracted with ether, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/methylene chloride=1/1) to give the desired compound methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-nitroacetate (0.08 g, 22%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].O[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[O:1][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:6]=[O:7]
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (3.0 g, 20 mmol) in anhydrous THF (100 mL), triphenyl phosphene (10.49 g, 40 mmol), 4-(2-hydroxyethyl)morpholine (5.25 g, 40 mmol) and N,N-diisopropylethylamine (7.76 g, 60 mmol) were added. To this stirred solution was added diethylazodicarboxylate (6.97 g, 40 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen and diluted with ethyl acetate (200 mL). The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel 230-400 mesh; 0-3% methanol in CH2Cl2 as eluent) to give 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (1.66 g, 32%) as an oil.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42]([NH:12][CH2:11][C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:46][CH:47]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)Cl)ccc2c1O
Reactant: NCc1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)NCc3cccc4ccccc34)ccc2c1O
Reaction time: 18 h

Procedure:
To a stirred solution of 44 μL of 1-naphthylmethylamine and 51 μL of diisopropylethylamine in 0.5 mL of pyridine is added 100 mg of 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-7-quinolinesulfonyl chloride from Preparation No. 31. After 18 h, the solution is added to 3.5 mL of rapidly stirred 2 N HCl, and the resulting solid is filtered, washed well with water, and dried under vacuum. Flash chromatography of the solid on silica gel using 2-5% methanol in dichloromethane provides 48 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoroaniline (25.0 g, 225 mmol) and potassium carbonate (47 g, 337 mmol) in water (112 mL) and acetone (45 mL) at 0° C. was added cinnamoyl chloride (37 g, 225 mmol, 1 eq) in acetone (45 mL) over 2 h. The reaction was stirred for 1 h @ 0° C., then quenched into 200 mL of ice-water. The white crystalline solid was filtered and washed with water. The solid was air dried for 2 h, then washed with 400 mL of hexanes. The solid was dried under vacuum overnight to afford product. 1 H NMR (400 MHz, CDCl3) δ ppm 8.49 (br t, J=7.8 Hz, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.57 (m, 3H), 7.41 (m, 3H), 7.17 (m, 3H), 6.61 (d, J=15.6 Hz, 1H). Mass Spectrum (ESI) m/e=242.1 (M+1).
Reaction SMILES: C[O:2][C:3]1[C:12]([C:13]2[O:17][C:16]([C@@H:18]([NH:28][C:29]([CH:31]3[CH2:34][N:33]([CH3:35])[CH2:32]3)=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH3:26])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:35][N:33]1[CH2:34][CH:31]([C:29]([NH:28][C@H:18]([C:16]2[O:17][C:13]([C:12]3[C:3](=[O:2])[NH:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:14][N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH3:26])=[O:30])[CH2:32]1
Reactant: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C)C1)c1ncc(-c2cc3ccccc3nc2OC)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C)C1)c1ncc(-c2cc3ccccc3[nH]c2=O)o1
Reaction time: 1 h

Procedure:
A solution of (S)-N-(1-(5-(2-methoxyquinolin-3-yl)oxazol-2-yl)-7-oxononyl)-1-methylazetidine-3-carboxamide (0.05 mmol, 1 eq), prepared as described above, in DCM (1 mL) was treated with 0.2 mL of HCl 4N in dioxane. The mixture was stirred 1 h at room temperatures, then concentrated and purified by RP-HPLC using water (+0.01% TFA) and MeCN (+0.01% TFA) as eluents (column C18). The pooled product fractions were lyophilized and the product was obtained as a white solid. MS (ES) C26H32N4O4 requires: 464.58, found: 465. 1H-NMR (400 MHz, DMSO-d6) δ: 12.21 (1 H, s), 9.83 (1 H, bs), 8.89-8.82 (1 H, m), 8.26 (1 H, s), 7.83 (1 H, d, J=7.6 Hz), 7.78 (1 H, s), 7.55 (1 H, t, J=7.2 Hz), 7.38 (1 H, d, J=8.4 Hz), 7.25 (1 H, t, J=7.6 Hz), 5.09 (1 H, bs), 4.36 (1 H, bs), 4.22-4.20 (1 H, m), 4.11 (1 H, bs), 3.98-3.92 (1 H, m), 3.57-3.55 (1 H, m, partially overlaps with water), 2.82 (3 H, s), 2.42-2.37 (4 H, m), 1.96-1.92 (1 H, m), 1.83-1.80 (1 H, m), 1.48-1.44 (2 H, m), 1.35-1.33 (4 H, m), 0.89 (3 H, t, J=7.2 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:3][CH:4]=3)[N:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:9]2=[O:21])=[CH:14][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
(±)-7-Chloro-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.13 g; 0.33 mmol) (from Example 1e supra) was combined with aniline (100 μL; 1.10 mmol) (Aldrich). The mixture was heated to 110° C. A clear solution resulted upon heating and then a new solid precipitated out of solution. Reaction mixture was cooled to room temperature after 45 minutes. The residue was triturated with hexanes and then purified by flash chromatography (Biotage, 40M, 40:60 to 50:50 ethyl acetate-hexanes gradient) to give (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid, after crystallization from ethyl acetate-hexanes. (Yield 21.6 mg; 14.8%). A substantial amount of (±)-3-(4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one adhered to the silica and was eluted with 50:50 ethyl acetate-methanol. (Yield 88 mg; 60%). Melting Point: 222–234° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:12]1([C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][C:2]#[N:1])[CH2:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCCCN1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCCCN1CC=C(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
N-(4-Aminobutyl)-4-phenyl-1,2,3,6-tetrahydropyridine (C) 1.8 g of lithium aluminium hydride are suspended in small portions (exothermic dissolution) in 50 ml of anhydrous THF (freshly distilled over sodium). 4.5 g of 4-(4-phenyl-1,2,3,6-tetrahydropyridinyl)butyronitrile, in solution in THF, are added dropwise at 0° C. and then reaction is allowed to take place at 0° C. for 3 hours with good stirring. The mixture is hydrolysed with a mixture of 5 ml of water in solution in 50 ml of THF and the combined mixture is allowed to stand overnight in order to agglomerate the precipitate. The precipitate is filtered on celite and the filtrate is dried over anhydrous sodium sulphate and concentrated. The residue is distilled under pump vacuum. A colourless oil is obtained. Y=86%. 1H NMR (CDCl3):1.26 (bs, 2H, --NH2), 1.43-1.66 (m, 4H, --H2C--CH2 --), 2.44-2.51 (t, 2H, --CH2 --) 2.59 (b s, 2H, --CH2 --), 2.68-2.76 (m, 4H, --CH2 --CH2 --) 3.15-3.19 (d, 2H, --CH2 --), 3.72-3.78 (q, 2H, --CH2 --), 6.06 (q, 1H, --CH=), 7.22-7.41 (m, 5H, phe). 13C NMR (CDCl3):24.6 (--CH2 --CH2 --CH2 --NH2), 28.1 (--CH2 --CH2 --NH2), 31.9 (--CH2 --CH2 --N<, pyrid), 42.2 (--CH2 --NH2), 50.4 (--CH2 --CH2 --N<, pyrid), 53.3 (=CH--CH2 --N<), 58.3 (>N--CH2 --), 121.9 (>CH--), 124.9 (>CH)2 --), 126.9 (>(CH)2 --), 128.2 (<C=CH--, pyrid), 135.0 (>C=CH--, pyrid), 140.9 (>C<).
Reaction SMILES: Br[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:10]([NH:12][C:13](=[O:15])[O-:14])[CH3:11].[OH:16][C:17]1[C:18]([Cl:30])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>CC#N.O.C(Cl)Cl>[CH2:10]([NH:12][C:13](=[O:14])[O-:15])[CH3:11].[CH2:2]([O:16][C:17]1[C:18]([Cl:30])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1)[CH3:3]
Reactant: CCBr
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOc1cc2c(cc1Cl)C(C)C1CNCC21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Bromoethane (17 mL, 0.23 mmol) and K2CO3 (105 mg, 0.75 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (44 mg, 0.15 mmol) in CH3CN (1.5 mL). The reaction was stirred overnight at 70° C., diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C17H22ClNO3+H: 324, observed: 324.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:11]=3[F:10])=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1F
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccc(F)cc1F
Yield: 45 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2,4-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 45% yield: mp 157-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.23 (m, 6H), 6.84-6.74 (m, 2H), 6.06 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.49 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.43 (t, J=8.4 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.1, 162.7, 160.8, 157.4, 155.3, 153.3, 135.5, 131.2, 128.9, 128.3, 128.0, 121.2, 117.0, 111.5, 103.9, 47.9, 42.0, 41.6, 37.4, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [H][H].Cl[C:4]1[N:9]=[C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16]>CO.[C].[Pd]>[N:9]1[CH:4]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=12
Reactant: COC(=O)c1cc2c(nc1Cl)CCCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2c(c1)CCCCC2
Yield: 100.2 %

Procedure:
After suspending 10% palladium-carbon (600.0 mg) in methanol (15.0 ml), the suspension was stirred at room temperature for 30 minutes in an atmosphere of hydrogen. A methanol solution (30.0 ml) of methyl 2-chloro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.00 g, 12.5 mmol) was added to the reaction solution and stirred at room temperature for 18 hours in an atmosphere of hydrogen. After removing the catalyst by filtration, the thus obtained residue was washed with methanol, the solvent was evaporated under reduced pressure and then the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (2.57 g, quantitative) as white powder
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][CH:22]1[O:27][CH:26]([CH3:28])[CH2:25][N:24]([CH2:29][C:30]([N:33]2[CH:37]=[C:36]([NH2:38])[N:35]=[CH:34]2)([CH3:32])[CH3:31])[CH2:23]1>>[CH3:28][CH:26]1[O:27][CH:22]([CH3:21])[CH2:23][N:24]([CH2:29][C:30]([N:33]2[CH:37]=[C:36]([NH:38][C:15](=[O:17])[CH:14]([NH:13][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:18][CH2:19][CH3:20])[N:35]=[CH:34]2)([CH3:32])[CH3:31])[CH2:25]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC1CN(CC(C)(C)n2cnc(N)c2)CC(C)O1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CC(C)OC(C)C2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-[2-(2,6-Dimethyl-morpholin-4-yl)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.1, 19.5, 25.9, 28.2, 28.9, 29.7, 36.6, 38.8, 53.0, 58.9, 61.0, 61.3, 68.5, 72.1, 74.4, 76.9, 77.3, 77.6, 100.8, 101.1, 101.3, 104.7, 110.7, 110.9, 117.9, 131.2, 137.3, 139.8, 159.8, 162.3, 172.3; MS m/z 518.2 (M+1).